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Linking the “two‐hit” response following injury to enhanced TLR4 reactivity
Author(s) -
Murphy Thomas J.,
Paterson Hugh M.,
Kriynovich Sara,
Zang Yan,
KurtJones Evelyn A.,
Mannick John A.,
Lederer James A.
Publication year - 2005
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0704382
Subject(s) - tlr4 , chemokine , proinflammatory cytokine , lipopolysaccharide , tumor necrosis factor alpha , inflammation , cytokine , immunology , biology , immune system , in vivo , toll like receptor , interleukin 10 , innate immune system , microbiology and biotechnology
Severe injury can initiate an exaggerated systemic inflammatory response and multiple organ failure (MOF) if a subsequent immune stimulus, “second hit”, occurs. Using a mouse thermal injury model, we tested whether changes in innate immune cell reactivity following injury can contribute to the development of heightened inflammation and MOF. Using high‐purity Escherichia coli lipopolysaccharide (LPS) to selectively stimulate Toll‐like receptor 4 (TLR4), we demonstrate augmented interleukin (IL)‐1β, tumor necrosis factor α (TNF‐α), and IL‐6 production by 1 day but particularly, at 7 days after injury. The in vivo significance of enhanced TLR4 responsiveness was explored by challenging sham or burn mice with LPS at 1 or 7 days after injury and determining mortality along with in vivo cytokine and chemokine levels. Mortality was high (75%) in LPS‐challenged burn but not sham mice at 7 days, although not at 1 day, after injury. Death was associated with leukocyte sequestration in the lungs and livers along with increased proinflammatory cytokine and chemokine levels in these organs. Blocking TNF‐α activity prevented this mortality, suggesting that excessive TNF‐α production contributes to this lethal response. These findings demonstrate the potential lethality of excessive TLR4 reactivity after injury and provide an explanation for the exaggerated inflammatory response to a second hit, which can occur following severe injury.